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The cytoskeleton, a complex network of protein filaments and crosslinking proteins, dictates diverse cellular processes ranging from division to cargo transport. Yet, the role the cytoskeleton plays in the intracellular transport of DNA and other macromolecules remains poorly understood. Here, using single-molecule conformational tracking, we measure the transport and conformational dynamics of linear and relaxed circular (ring) DNA in composite networks of actin and microtubules with variable types of crosslinking. While both linear and ring DNA undergo anomalous, non-Gaussian, and non-ergodic subdiffusion, the detailed dynamics are controlled by both DNA topology (linear vs. ring) and crosslinking motif. Ring DNA swells, exhibiting heterogeneous subdiffusion controlled via threading by cytoskeleton filaments, while linear DNA compacts, exhibiting transport via caging and hopping. Importantly, while the crosslinking motif has little effect on ring DNA, linear DNA in networks with actin–microtubule crosslinking is significantly less ergodic and shows more heterogeneous transport than with actin–actin or microtubule–microtubule crosslinking.
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This content will become publicly available on March 1, 2026
DNA Transport is Topologically Sculpted by Active Microtubule Dynamics
The transport of macromolecules, such as DNA, through the cytoskeleton is critical to wide-ranging cellular processes from cytoplasmic streaming to transcription. The rigidity and steric hindrances imparted by the network of filaments comprising the cytoskeleton often leads to anomalous subdiffusion, while active processes such as motor-driven restructuring can induce athermal superdiffusion. Understanding the interplay between these seemingly antagonistic contributions to intracellular dynamics remains a grand challenge. Here, we use single-molecule tracking to show that the transport of large linear and relaxed circular DNA through motor-driven microtubule networks can be non-Gaussian and multimodal, with the degree and spatiotemporal scales over which these features manifest depending nontrivially on the state of activity and DNA topology. For example, active network restructuring increases caging and non-Gaussian transport modes of linear DNA, while dampening these mechanisms for circular DNA. We further discover that circular DNA molecules exhibit either markedly enhanced subdiffusion or superdiffusion compared to their linear counterparts, in the absence or presence of kinesin activity, indicative of microtubules threading circular DNA. This strong coupling leads to both stalling and directed transport, providing a direct route towards parsing distinct contributions to transport and determining the impact of coupling on the transport signatures. More generally, leveraging macromolecular topology as a route to programming molecular interactions and transport dynamics is an elegant yet largely overlooked mechanism that cells may exploit for intracellular trafficking, streaming, and compartmentalization. This mechanism could be harnessed for the design of self-regulating, sensing, and reconfigurable biomimetic matter. Published by the American Physical Society2025
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- PAR ID:
- 10595650
- Publisher / Repository:
- Americal Physical Society
- Date Published:
- Journal Name:
- PRX Life
- Volume:
- 3
- Issue:
- 1
- ISSN:
- 2835-8279
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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